Dialkylaminoalkyl amides of alpha, alpha-diaryltoluic acids and their salts



Patented May 11, 1954 UNITED STATES PATENT OFFICE DIALKYLAMINOALKYL AMIDES oF age-n1- ARYLTOLUIC ACIDS AND THEIR SALTS Carl Peter Krimmel, Mundelein, Ill., assignor to G. D. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application May 7, 1951, Serial No. 225,059

16 Claims. (01'. 260-389) February 21, 1950. s V

have provided new compositions of matter which may be represented By this invention I by the following structural formula Ar Ar-- H R -o ONH-AlkN wherein Arand Ar are lower aromatic groups, wherein All: is a lower alkylene radical, and wherein R. and R are lower alkyl groups,

In the foregoing structural formula Ar and Ar may represent such lower aromatic groups as phenyl; o, m-, and p-tolyl; m-, and p-chlorophenyl; o-, m-, and p-anisyl and the like. The Alk group represents bivalent, saturated, aliphatic hydrocarbon radicals of from two to eight carbon atoms. These radicals are derived from straightchain or branched-chain aliphatic hydrocarbons and include radicals such as ethylene, propylene, butylene, amylene, and polymethylene radicals such as trimethylene, tetramethylene, pentamethylene, and hexamethylene.

'Among the radicals which R and B. may represent are such lower alkyl groups as methyl, ethyl, propyl, butyl, amyl, hexyl, cyclopentyl, and cyclehexyl, wherein the propyl, butyl, amyl, and hexyl groups may be either of the straight-chain or branched-chain type.

' methyliodide, chloride and bromide, ethyl chloride, propyl bromide, butyl chloride, isobutyl chride, benzyl chloride and bromide, phenethyl bromide, naphthylmethyl chloride, dimethyl suliate, diethyl sulfate, methyl benzenesulfonate,

ethyl toluenesulfonate, ethylene chlorohydrin, propylene .chlorohydrin, allyl chloride, meth" allyl bromide and crotyl bromide.

The amides of this invention have been found to possess a number of highly useful therapeutic properties. Thus they have been shown to be active spasmolytics, diuretics, and cardiovascular agents.

The acids which constitute the starting materials for the amides of this invention are prepared by conventional methods such as that of Drory (Ber. Deut. Chem. Ges. 24, 2572; 1891). Thus a,udiphenyl-o-toluic acid, M. P. 161-164 0., is prepared by causing o-cyanobenzal chloride, benzene, and aluminum chloride to react to obtain o-cyano-triphenylmethane which is hydrolyzed to the acid with 25 alcoholic potassium hydroxide. The o-cyanobenzal chloride is conveniently obtained by the chlorination of o-toluonitrile by ultraviolet radiation. In the same manner, starting with m-toluonitrile and p-toluonitrile, 0:,oc-diDh8IlY1-l'Il-t01lli0 acid, M. P. ISO-182 C. and u,a-diphenyl-p-toluic acid, M. P. 163-165" C. are respectively obtained.

My invention will be described more fully in conjunction with the following examples. It should be understood, however, that these examples are given by way of illustration only and that the invention is not to be construed as limited in spirit or in scope by the details set forth. It will be apparent to those skilled in the art that many modifications in materials and methods may be made without departing from the invention. In each of these examples, temperatures are given in degrees centigrade, C.) parts by weight are given in grams (g.), and parts by volume in milliliters (ml.).

v EXAMPLE 1 p-Diethylaminoethyl amide of a,a-dz'phenyl-o- V toluic acid A mixture of 40 g. of a,a-diphenyl-o-toluic'acid, 300 m1. of carbon tetrachloride, and 40 ml. of

' thionyl chloride was refluxed on the steam bath for three hours. The excess of the volatile reagents was then removed under vacuum, the residue was taken up in 1000 ml; of anhydrous ethyl ether, and 16.2 g. of fl-diethylaminoethylamine were added. The resultant precipitate was removed from the reaction mixture by filtration, treated with water, and made alkaline with potassium hydroxide. The base,'which was released in solid form, was extracted with ether, the ether extract was dried over anhydrous potassium carbonate, filtered, and stripped of ether on the steam bath. The residual syrup crystallized upon standing. Recrystallization from petroleum ether gave 26 g. of white granular material, which on analy sis was shown to contain 7.14% nitrogen (calculated 7.25% N).

To a solution of g. of the basic diethylaminoethyl amide of u,o-dipheny1-o-toluic acid in 50 ml. of butanone were added 9.5 ml. of a 10% solution of hydrogen chloride in anhydrous isopropanol. The resultant white crystalline precipitate of the hydrochloride, after recrystallization from butanone, melted at 197-199".

,8 (a,a-DiphenyZ-o-toluamido) ethyltrieihylammonium bromide A mixture of g. of the c-diethylaminoethyl amide of a,a-diphei1yl-0-to1uic acid, 8.7 g. of ethyl bromide, and 15 ml. of butanone was placed in a shielded pressure bottle and heated in a steam bath for three hours. The crystals which separated from the cooled reaction mixture were filtered, washed with butanone, and .dried in the steam cabinet. The 16 g. of the quaternary salt, melting at 251-255" with decomposition, may be recrystallized from absolute ethanol to obtain a product melting at 254-256 with decomposition. It has the formula CaHs C aH5 C H EXANIPLE 3 -Dimethylaminopropyl amide of a,u-diphenylo-toluic acid A mixture of g. of a,a-diphenyl-o-toluic acid, 200 ml. of carbon tetrachloride, and 30 ml. of thionyl chloride was refluxed on the steam bath for three hours. The excess of volatile reagents was then removed under vacuum, the residue was taken up in 800 ml. of anhydrous ethyl ether, and 14.3 g. of v-dimethylamino-propylamine were added. The reaction mixture was extracted with dilute hydrochloric acid and the extract was made alkaline with potassium hydroxide. The orange oil which separated crystallized on standing to a granular solid. After successive recrystallizations from a solution of ethyl ether-petroleum ether and petroleum ether, a white crystalline powder was obtained. Analysis: Calculated, basic N=3.'76%. Found, basic N: 3.76%.

To a solution of 6.5 g. ,of the 'y-dimethylaminopropyl amide of a,a-diphenyl-o-toluic acid in 100 ml. of anhydrous ether were added 6.2 ml. of a 10% solution of hydrogen chloride in isopropanol. The tacky deposit of the hydro-chloride was washed by ether decantation and then heated with 100 ml. of butanone. This caused the hydrochloride .to separate as a crystalline powder which, after filtration and air drying, weighed 5.3 g. and melted at 1'72175.

made alkaline with sodium hydroxide, the released oil wasextracted with ether, the extract was dried over anhydrous potassium carbonate, the ether was stripped on the steam bath, and the residue was vacuum distilled to yield 25 g. of viscous oil'boiling at about 23l-241 and 0.3 pressure.

To a solution of 10 g. of the above v-diethylaminopropyl amide of a,a-diphenyl-o-toluic acid in 40 ml. of acetone were added 9.1 m1. of a 10% solution of hydrogen chloride in anhydrous isopropanol. After intimate mixing, 1000 ml. of anhydrous ethyl ether were added to yield an initial gummy deposit which became crystalline upon standing. Filtration and air drying gave 9.5 g. of a white hydrochloride melting at EXAMPLE 5 'y (a,0c Diphenyl o toluamidomro'pyltrieth ylammoniam bromide A mixture of 12 g. of the -diethylaminopropyl amide of a,a-diphenyl-o-toluic acid, 6.6 g. of ethyl bromide, and 20 m1. of butanone was placed in a shielded pressure bottle and heated in a steam bath for three hours. "The crystals which separated from the cooled reaction mixture were filtered, washed with butanone and recrystallized from isopropanol to give 7.5 g. of white crystals having a melting point of 193-195.

EXAMPLE 6 a-Dieihylamino-a-methylbatyl amide of a,a-diphenyZ-o-toluic acid A solution of 60 g. of u, x-diphenyl-o-toluic acid, 60 ml. of thionyl chloride, and 400 ml. of [carbon tetrachloride was refluxed on the steam bath for three hours. The excess volatile reagents were removed by vacuum distillation on the steam bath. The residue was dissolved in 300 ml. of acetone and 33.2 g. of. E-diethylamino- 2-aminopentane were added dropwise with stirring. The reaction mixture was refluxed for three hours, and the acetone was removed by vacuum distillation on the steam bath. The residue was taken up in water, ether washed, made alkaline with potassium hydroxide and ether extracted. The extract was separated, dried over anhydrous potassium carbonate, filtered and ether stripped. Vacuum distillation of the residue yielded 60.6 g. of pale yellow syrup boiling at about 260-265 C. and 2mm. pressure.

EXAMPLE '7 -Dimethylaminopropyl amide of aux-(Zi- (o-tolyl) -o-toluic acid A mixture of 33 g. of a,a-di-(Ot0iy1)-0-t01ulc acid, 250 ml. of carbon tetrachloride, and 30 ml. of thionyl chloride was refluxed on the steam bath for three hours. After removal of the excess of the volatile reagents by vacuum distillation, the residue was taken up in 800 ml. of anhydrous ether and 14.4 g. of -dimethylaminopropy1amine were added. The reaction mixture was extracted with dilute hydrochloric acid and the extract made alkaline with sodium hydroxide. Purificain the previous examples.

o toluic acid, was readily soluble in ether and related organic solvents.

EXAMPLE 8 :p-Diethylaminoethyl amide of cam-(1K1)- am'syl) --tolaic acid i A mixture of 24 g. of a,a-di-(p-anisyl) -o-tolu1c acid, 175 ml. of carbon tetrachloride and ml. of thionyl chloride was refluxed on the steam bath for three hours. The excess of the volatile reagents was then removed under vacuum, the residue was taken u in anhydrous ether, and 8.1 g. of B-diethylaminoethylamine were added. The reaction mixture was extracted with dilute hydrochloric acid and the base liberated by treatment with alkali. Purification was carried out by the usual methods. The product, the B- diethylaminoethyl amide of a,a-di-(p-anisyl)-otoluic acid, was readily soluble in ether and related organic solvents.

EXAMPLE 9 fl-Diisopropylaminoethyl amide of madz'phenyZ-m-toluic acid A solution of 30 g. of a,a-diphenyl-m-toluic acid in 100 ml. of carbon tetrachloride was treated with 15 ml. of thionyl chloride and maintained at reflux temperature for 2 hours. The excess of volatile material was then removed under vacuum and the residue dissolved in 500 ml; of ether. To this solution 6.5 g. of Bdiisopropylaminoethylamine were added dropwise with stirring. The precipitate was extracted with water. The aqueous layer was separated, rendered alkaline by addition of sodium hydroxide and extracted with ether. The ether extract was dried over anhydrous potassium carbonate, stirred with decolorizing charcoal, filtered, and evaporated. The 18-diisopropylaminoethylamide of cad-diphenyl-m-toluic acid remained as a pale, viscous syrup. It has the structural formula CH(OH:)2 do-nn-om-pra-N omen):

. EXAMPLE 10 p-Diethylaminoethyl amide of ,0;-

diphenyZ-p-tolaic acid The acid chloride residue obtained from 29 g. of u,a-diphenyl-ptoluic acid and 11.6 g. of 2- diethylaminoethylamine were caused to react under the same conditions as in Example 8. The resultant B-diethylaminoethyl amide of (La-d1" phenyl-p-toluic acid was collected at about 258- 264" C. at 0.5 mm. pressure. It-was obtained as asyrup whichcrystallized upon standing.

To a solution of 10 g. of the fi-diethylaminoethyl amide of a,a-diphenyl-,p-toluic acid in 1000 ml. of anhydrous ethyl ether was slowly added with stirring an equivalent of hydrogen chloride as a solution in anhydrous isopropanol. ,A tacky whitedeposit was formed. The ether was decanted, and the tacky deposit taken up in boiling Jbutanone and decolorized with charcoal.

Cooling yielded 1.8g.- of a white,- crystalline,

6 water-soluble powder melting 'at'14'7 149PC." It has the structural formula I CoHs CtHs-(JH EXAMPLE 11 -Diethylaminopropyl amide of 11,0:-

diphenyZ-p-toluz'c acid A solution of 29 g. of a,a-diphenyl-p-toluic acid, 30 ml. of thionyl chloride, and 200 ml. of carbon tetrachloride .was refluxed on the's'team bath for two hours. The excess volatile reagents were removed by vacuum distillation on the steam bath. The residue was dissolved in 200 m1. of acetone and 13 g. of 'y-diethylaminoprop-ylamine were added dropwise with stirring. The reaction mixture was refluxed for three hours and the acetone was removed by vacuum distillation on the steam bath. The residue was taken up in water and ether extracted. The aqueous layer was separated, made alkaline with otassiumhydroxide and ether extracted. The ether extract was dried over anhydrous potassium carbonate, filtered, and ether stripped. Vacuum distillation of the residue yielded 23 g. of the 'y-diethylaminopropyl amide of a,a-diphenyl-p-tolulc acid which'was collected from 274-279 C. and 1.0 mm. pressure as a yellow syrup. 1

An equivalent of hydrogen chloride gas, as a 25% solution in anhydrous isopropanol, was added to 13 g. of the v-diethylaminopropyl amide of a,a-diphenyl-p-toluic acid dissolved in 40 ml. of butanone. The solution was refrigerated and seeded. Seed crystals were obtained by refrigeration of a small sample of the butanone solution and dilution with anhydrousqethyl ether. The precipitated hydrochloride Was recrystallized from butanone and was obtained as 10.2 glof a white, water-soluble, crystalline powder melting at PTO-172.

I claim:

1. A member of the class of compounds consisting of dialkylaminoalkyl amides of an 11,0- diaryl substituted toluic acid of the structural formula Ar H wherein Ar and Ar are lower aryl hydrocarbon .radicals containing 6 to 10 'carbon1atoms, Alk

is a lower alkylene radical. containingat least'2 carbon atoms, and R and R are lower alkyl radicals.

3. A dialkylaminoalkyl amide of a,a-diphenylo-toluic acid of the structural formula wherein Alk is a lower alkylene radical containing at least 2 carbon atoms, and R. and R are lower alkyl radicals.

4.:A diethylaminoalkyl amide of a,a-diphenylo-toluic acid of the structural formula CuHb Calla-"( 1H wherein All: is a lower alkylene radical containing at least'2 carbon atoms.

5. A dialkylaminoalkyl amide of an u,a-diaryl substituted p-toluic acid of the structure formula wherein Ar and Ar are loweraryl hydrocarbon radicals containing 6 to 10 carbon atoms, Alk is a lower alkylene radical containing at least 2 carbon atoms, and R and R are lower alkyl radicals.

6. A dialkylaminoalkyl amide of a,a-diphenylp-toluic acid of the structural formula wherein Alk is a lower alkylene radical containing at least 2 carbon atoms, and R. and R" are lower alkyl radicals.

7. A diethylaminoalkyl amide of a,u-diphenylp-toluic acid of the structural formula wherein All: is a lower alkylene' radical containing at least 2 carbon atoms.

8. An (can: diaryltoluamidoalkyl)trialkylammonium salt of the structural formula l Ar-CH "wherein Ar and Ar are lower aryl hydrocarbon wherein Alk is a lower alkylene radical containing at least 2 carbon atoms and R,-R', andr-R" are lower alkyl radicals and X is one equivalent of an anion.

10. An (0:,oa -,diphenyltoluamidoalkyl)diethylalkylammonium salt of the structural formula C aHr- H -o ONH-Alk-N( 02m) 2:RX

wherein Alk is a lower alkylene radical containing at least 2 carbon atoms, R is a lower alkyl radical, and X is one equivalentof an anion.

11. An (can: dip-henyl o toluamidoalkyl) diethylalkylammonium salt of the structural formula CeHs wherein Alk is a lower alkylene radical containing at least 2 carbon atoms, R. is a lower alkyl radical, and X is one equivalent of an anion.

CeHs- I H CoHs 'C H 'CH C sHa CaHs C BBS-1 H wherein vX is a halide ion.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,009,144 Miescher et a1 July 23, 1935 2,302,805 Schussler Nov. 24, 1942 OTHER REFERENCES .-Jones et al.--J0ur. Am. Chem. Soc., vol. 48, pages 188, 192, January 1926. 

1. A MEMBER OF THE CLASS OF COMPOUNDS CONSISTING OF DIALKYLAMINOALKYL AMIDES OF AN A,ADIARYL SUBSTITUTED TOLUIC ACID OF THE STRUCTURAL FORMULA 